Transdermal delivery of analgesics

ABSTRACT

The present invention provides a transdermal drug delivery system which comprises: a therapeutically effective amount of an analgesic; at least one dermal penetration enhancer, which is a safe skin-tolerant ester sunscreen ester; and at least one volatile liquid. The invention also provides a method for administering at least one systemic acting analgesic to an animal which comprises applying an effective amount of the analgesic in the form of the drug delivery system of the present invention.

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/910,780, filed Jul. 24, 2001, which is adivisional of U.S. Pat. No. 6,299,900, filed Dec. 18, 1998 as the U.S.national stage application of PCT application PCT/AU97/00091, filed Feb.19, 1997. The entire contents of each of U.S. patent application Ser.No. 09/910,780, U.S. Pat. No. 6,299,900, and PCT applicationPCT/AU97/00091 are incorporated herein by reference, and priority toeach is claimed under 35 U.S.C. § 119 and/or § 120.

FIELD OF THE INVENTION

[0002] The present invention relates to transdermal drug delivery. Morespecifically, the invention relates to a topical absorption/penetrationenhancing agent for use in the delivery of analgesics and analgesicderivatives to an animal, including a human. The invention also relatesto a system for the non-occlusive delivery to an animal of analgesicsand analgesic derivatives across a dermal surface of the animal.Transdermal drug formulations of the present invention may be used forsystemic delivery.

BACKGROUND OF THE INVENTION

[0003] There is a constant need for methods for the safe and effectiveadministration of physiologically active agents, such as analgesics. Formany medications it is important that the administration regime is assimple and non-invasive as possible in order to maintain a high level ofcompliance by a patient. Oral administration is one administrationregime that is commonly used because it is a relatively simple regime tofollow. However, the oral administration route is also complicatedbecause of complications associated with gastrointestinal irritation.

[0004] Many opioid analgesics such as fentanyl are subject to extensivefirst-pass metabolism which means oral bioavailability is often low andvariable and therefore not a viable route of administration.Additionally, these types of drugs have a short half life and thusmultiple daily dosing is required.

[0005] Administration of physiologically active agents through the skin(‘transdermal drug delivery’) has received increased attention becauseit not only provides a relatively simple dosage regime but it alsoprovides a relatively slow and controlled route for release of aphysiologically active agent into the systemic circulation. However,transdermal drug delivery is complicated by the fact that the skinbehaves as a natural barrier and therefore transport of agents throughthe skin is a complex mechanism.

[0006] Structurally, the skin consists of two principle parts, arelatively thin outermost layer (the ‘epidermis’) and a thicker innerregion (the ‘dermis’). The outermost layer of the epidermis (the‘stratum corneum’) consists of flattened dead cells which are filledwith keratin. The region between the flattened dead cells of the stratumcorneum are filled with lipids which form lamellar phases that areresponsible for the natural barrier properties of the skin.

[0007] For effective transdermal delivery of a physiologically activeagent that is applied to the surface of the skin (‘topicalapplication’), the agent must be partitioned firstly from the vehicleinto the stratum corneum, it must typically then be diffused within thestratum corneum before being partitioned from the stratum corneum to theviable epidermis and then into the dermal circulation.

[0008] To overcome some of the problems with transdermal delivery thatare associated with transport across the dermal layers (‘percutaneousabsorption’), physiologically active agents are commonly formulated withincorporation of one or more dermal penetration enhancers (Finnin andMorgan, J. Pharm. Sci., Vol 88, No. 10, October 1999, pp. 955-958) whichare often lipophilic chemicals that readily partition into the stratumcorneum whereupon they exert their effects on improving the transport ofdrugs across the skin barrier.

[0009] There is a need for improvements in the transdermal delivery ofanalgesics.

SUMMARY OF THE INVENTION

[0010] According to the present invention there is provided atransdermal drug delivery system comprising:

[0011] (a) a therapeutically effective amount of an analgesic;

[0012] (b) at least one dermal penetration enhancer, which is a safeskin-tolerant ester sunscreen of formula (I):

[0013] wherein

[0014] R¹ is hydrogen, lower alkyl, lower alkoxy, halide, hydroxy or NR³R⁴;

[0015] R² is a C₈to C₁₈ alkyl;

[0016] R³ and R⁴ are each independently hydrogen, lower alkyl or R³ andR⁴ together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclic ring;

[0017] n is 0 or 1, and

[0018] q is 1 or 2,

[0019] wherein, when n is 0 and R¹ is NR³ R⁴, then NR³ R⁴ ispara-substituted, and

[0020] wherein said dermal penetration enhancer is present in an amountof from about 10 to about 10,000 wt % based on the weight of theanalgesic; and

[0021] (c) at least one volatile liquid.

[0022] In addition to providing improved percutaneous absorptionefficiency, the composition of the invention may also provide lowerirritancy than some other more occlusive delivery systems such astransdermal patches, because the composition is non-occlusive to theskin.

[0023] More preferably the dermal penetration enhancer is selected fromthe group consisting of a C₈ to C₁₈ alkyl para-aminobenzoate, C₈ to C₁₈alkyl dimethyl-para-aminobenzoate, C₈ to C₁₈ alkyl cinnamate, C₈ to C₁₈alkyl methoxycinnamate or C₈ to C₁₈ alkyl salicylate. Most preferablythe dermal penetration enhancer is octyl salicylate (2-ethylhexylsalicylate, octisalate), octyl dimethyl para-aminobenzoate or octylpara-methoxycinnamate (Padimate O).

[0024] The drug delivery systems according to the invention may compriseone or more analgesics together with the penetration enhancerincorporated into a dosage form for topical application to the skin ofanimals. Suitable dosage forms include creams, lotions, gels, ointments,mousses, sprays, aerosols, or any one of a variety of transdermaldevices for use in the continuous administration of systematicallyactive drugs by absorption through the skin. Some examples of suitablevehicles are given in U.S. Pat. Nos. 3,598,122, 3,598,123, 3,742,951,3,814,097, 3,921,636, 3,993,072, 3,993,073, 3,996,934, 4,031,894,4,060,084, 4,069,307, 4,201,211, 4,230,105, 4,292,299, 4,292,303,5,323,769, 5,023,085, 5,474,783, 4,941,880 and 4,077,407. Thesedisclosures are thus hereby incorporated herein by reference.

[0025] Optionally the drug delivery system may contain pharmaceuticalcompounding agents, such as one or more thickening agents such ascellulosic thickening agents, ethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, povidone, polyacrylic acids such ascarbopol, Sepigel® (polyacrylamide/isoparaffin/laureth-7), the Gantrez®series of polymethyl vinyl ether/maleic anhydride copolymers such as thebutyl ester of PVMIMA copolymer Gantrez® A-425, and any thickening agentknown in the art that has good compatibility with the volatile liquidand enhancers of the present invention.

[0026] Analgesics that may be used in the drug delivery system of thepresent invention include any systemically active analgesics which arecompatible with the dermal penetration enhancers of the presentinvention and which can be delivered through the skin with theassistance of the dermal penetration enhancer to achieve a desiredeffect. Suitable analgesics include the opioid analgesics such asbuprenorphine, butorphanol, dextromoramide, dezocine,dextropropoxyphene, diamorphine, fentanyl, alfentanil, sufentanil,hydrocodone, hydromorphone, ketobemidone, levomethadyl acetate,mepiridine, methadone, morphine, nalbuphine, opium, oxycodone,papaveretum, pentazocine, pethidine, phenoperidine, piritramide,dextropropoxyphene, remifentanil, tilidine, tramadol, codeine,dihydrocodeine, meptazinol, dezocine, eptazocine and flupirtine.

[0027] In one preferred form of the invention the drug delivery systemcomprises on a weight basis from about 1 to about 10% of the analgesic,from about 1 to about 10% of the dermal penetration enhancer and fromabout 80 to 99.8% ethanol, isopropanol or mixture thereof.

[0028] In another preferred form of the invention the drug deliverysystem comprises, on a weight basis, from about 1 to 5% of an analgesic,from about 1 to 5% of the dermal penetration enhancer, from about 45 to90% ethanol, isopropanol or mixture thereof, 5 to 45% water; andoptionally 0.5 to 5% of a thickening agent.

[0029] Whilst it is preferred that the analgesic and penetrationenhancer be delivered by simultaneous administration, the penetrationenhancer may be applied before or after the application of theanalgesic, if desired.

[0030] The present invention also provides a method for administering atleast one systemic acting analgesic to an animal which comprisesapplying an effective amount of the analgesic in the form of the drugdelivery system of the present invention.

[0031] Preferably the animal is a human but the invention also extendsto the treatment of non-human animals.

[0032] Preferably the drug delivery system is not supersaturated withrespect to the analgesic. As the volatile liquid of the drug deliverysystem evaporates, the resulting non-volatile composition is rapidlydriven into the dermal surface. It is possible that as the volatileliquid evaporates, the non-volatile dermal penetration enhancer becomessupersaturated with respect to the analgesic. However, it is preferredthat any supersaturation does not occur before transport of theresulting non-volatile composition across the epidermal surface hasoccurred.

[0033] It is most desirable that, after application of the drug deliverysystem, the volatile component of the delivery system evaporates and thearea of skin to which the drug delivery system was applied becomestouch-dry. Preferably said area of skin becomes touch-dry within 10minutes, more preferably within 3 minutes, most preferably within 1minute.

[0034] The group of dermal penetration enhancing ester sunscreencompounds of the present invention are particularly suitable fortransdermal delivery analgesics through the skin of an animal. Thesedermal penetration enhancing compounds are of low toxicity to the skinand are excellent promoters of percutaneous absorption.

[0035] Preferred volatile liquids of the present invention include safeskin-tolerant solvents such as ethanol and isopropanol. An aerosolpropellant, such as dimethyl ether, may constitute a volatile liquid forthe purpose of the present invention.

[0036] Surprisingly the group of dermal penetration compounds identifiedenhance the absorption of analgesics through the skin while avoiding thesignificant pharmacological disadvantages and toxicities of prior artenhancers. Additionally, the group of compounds of the inventionsurprisingly exhibit appreciable penetration into and substantivity forthe outer layers of the skin, namely the stratum corneum which haspreviously presented a formidable barrier to percutaneous drugabsorption.

[0037] In drug delivery systems according to the present invention apharmaceutical compounding agent, co-solvent, surfactant, emulsifier,antioxidant, preservative, stabiliser, diluent or a mixture of two ormore of said components may be incorporated in these systems as isappropriate to the particular route of administration and dosage form.The amount and type of components used should be compatible with thedermal penetration enhancers of this invention as well as with theanalgesic. A co-solvent or other standard adjuvant, such as asurfactant, may be required to maintain the analgesic in solution orsuspension at the desired concentration.

[0038] The pharmaceutical compounding agents can include paraffin oils,esters such as isopropyl myristate, ethanol, silicone oils and vegetableoils. These are preferably used in the range 1 to 50%. Surfactants suchas ethoxylated fatty alcohols, glycerol mono stearate, phosphate esters,and other commonly used emulsifiers and surfactants preferably in therange of 0.1 to 10% may be used, as may be preservatives such ashydroxybenzoate esters for preservation of the compound preferably inamounts of 0.01 % to 0.5 %. Typical co-solvents and adjuvants may beethyl alcohol, isopropyl alcohol, acetone, dimethyl ether and glycolethers such as diethylene glycol mono ethyl ether. These may be used inamounts of 1 to 50%.

[0039] Because of the effect of the penetration enhancer of theinvention, the dosage of the analgesic may often be less than thatconventionally used. It is proposed that, a dosage near the lower end ofthe useful range of the particular analgesic may be employed initiallyand increased as indicated from the observed response if necessary.

[0040] The concentration of analgesic used in the drug delivery systemwill depend on its properties and may be equivalent to that normallyutilised for the particular analgesic in conventional formulations. Boththe amount analgesic and the amount of penetration enhancer will beinfluenced by the type of effect desired.

[0041] Where it is desired to achieve higher systemic concentration ofan analgesic, proportionately higher concentrations of the enhancer ofthe invention may be required in the transdermal drug delivery system ofthe present invention, and the amount of analgesic included in thecomposition should be sufficient to provide the blood level desired.

[0042] The concentration of absorption/penetration enhancer may be inthe range from 10-10,000 weight percent of absorption/penetrationenhancer based upon the weight of analgesic. The ratio of penetrationenhancer to analgesic may vary considerably and will be governed as muchas anything, by the pharmacological results that are required to beachieved. In principle, it is desirable that as little absorptionenhancer as possible is used. On the other hand, for some analgesics, itmay well be that the upper range of 10,000% by weight will be required.It is preferred that the penetration enhancer and analgesic are inapproximately equal proportions.

[0043] A particular advantage of the drug delivery system of the presentinvention is that patient compliance is improved as the system does notocclude the skin. As a result local irritation and allergicsensitization problems arising from prolonged exposure of the skin toboth the delivery system of occlusive transdermal patch devices and theadhesive used to affix these patches to the skin are reduced.

[0044] The following definitions apply through this description and theclaims which follow.

[0045] The terms “percutaneous” and “transdermal” are used herein in thebroadest sense to refer to being able to pass through unbroken skin.

[0046] The term “dermal penetration enhancer” is used herein in itsbroadest sense to refer to an agent which improves the rate ofpercutaneous transport of active agents across the skin or use anddelivery of active agents to organisms such as animals, whether it befor local application or systemic delivery.

[0047] The term “non-occlusive” is used herein in its broadest sense torefer to not trapping or closing the skin to the atmosphere by means ofa patch device, fixed reservoir, application chamber, tape, bandage,sticking plaster, or the like which remains on the skin at the site ofapplication for a prolonged length of time.

[0048] The term “stratum corneum” is used herein in its broadest senseto refer to the outer layer of the skin, which is comprised of(approximately 15) layers of terminally differentiated keratinocytesmade primarily of the proteinaceous material keratin arranged in a‘brick and mortar’ fashion with the mortar being comprised of a lipidmatrix made primarily from cholesterol, ceramides and long chain fattyacids. The stratum corneum creates the rate-limiting barrier fordiffusion of the active agent across the skin.

[0049] The term “skin-depot” is used herein in its broadest sense torefer to a reservoir or deposit of active agent and dermal penetrationenhancer within the stratum corneum, whether it be intra-cellular(within keratinocytes) or inter-cellular.

[0050] The term “volatile: non-volatile liquid vehicle” is used in theart to refer to a liquid pharmaceutical vehicle comprising a volatileliquid mixed with a non-volatile liquid vehicle, such as a dermalpenetration enhancer. A system or vehicle comprising a volatile liquidmixed with a non-volatile dermal penetration enhancer when describedherein is used in its broadest sense to include those systems known asvolatile:non-volatile liquid vehicles.

[0051] Alkyl and alkoxy groups referred to herein may be either straightchain or branched. The term “lower alkyl” means alkyl groups containingfrom 1 to 5 carbon atoms. The term lower alkoxy has a similar meaning.The term “long chain alkyl” means alkyl groups containing from 5 to 18carbon atoms, more preferably 6 to 18 carbon atoms. The term “halide”means fluoride, chloride, bromide or iodide. The term “heterocyclicring” is herein defined to mean a ring of carbon atoms containing atleast one hetero atom, and further the ring may be saturated orunsaturated to any allowable degree.

[0052] The term “sunscreen” is used herein in its broadest sense torefer to a chemical agent capable of filtering out ultraviolet light.

[0053] The drug delivery system of the present invention enables a widerange of analgesics to be delivered through the skin to achieve adesired systemic effect. The drug delivery system preferably comprisesthe analgesic intimately mixed with a non-volatile dermal penetrationenhancer and a volatile liquid. Where the drug delivery system isapplied to the skin, the analgesic and non-volatile liquid arethermodynamically driven into the skin as the volatile liquidevaporates. Once within the skin the non-volatile liquid may eitherdisrupt the lipid matrix and/or act as a solubilizer to allow anenhanced penetration rate of the analgesic through the skin and into thesubject being treated. In this way, the dermal penetration enhancer actsas a vehicle and many systemic active analgesics are able to betransdermally administered to an animal.

[0054] It is believed that the non-volatile dermal penetration enhanceris readily absorbed into the stratum corneum in sufficient quantities toform a reservoir or depot of the dermal penetration enhancer within thestratum corneum. The dermal penetration enhancer also contains theanalgesic to be administered and as the dermal penetration enhancercrosses through the skin to form the skin-depot, the analgesic containedtherein is transported through the skin and contained within the depot.These depots are believed to form within the lipid matrix of the stratumcorneum wherein the lipid matrix creates a rate-limiting barrier fordiffusion of the analgesic across the skin and allows the dermallyadministered analgesic to be systemically released over a period oftime, usually up to 24 hours.

[0055] Once the volatile liquid of the drug delivery system hasevaporated, driving the mixture of non-volatile dermal penetrationenhancer and analgesic into the stratum corneum, the outer surface ofthe skin is then substantially free of analgesic and non-volatile dermalpenetration enhancer. Normal touching, wearing of clothes, rinsing oreven washing of the skin will not, to any significant extent, affectdelivery of the analgesic or displace either the analgesic or thenon-volatile dermal penetration enhancer, once the volatile liquid hasevaporated.

[0056] This is in contrast to prior-art systems where supersaturatedsolutions are used to increase the rate of drug permeation across theskin. Such supersaturated solutions are susceptible of readyprecipitation and require stabilization, such as with polymers, orprotection from external surfaces or objects which may effectnucleation.

[0057] The rate of absorption of the analgesic via the stratum corneumis increased by the non-volatile dermal penetration enhancer. Theanalgesic may be dissolved or suspended in the dermal penetrationenhancer at the time when it is being transported from the surface ofthe skin and into the stratum corneum. The performance of the dermalpenetration enhancer to deliver a desired analgesic varies withdifferences in both the nature of the dermal penetration enhancer andthe analgesic. It is understood that different dermal penetrationenhancers may need to be selected to be appropriate for delivery ofvarious analgesics.

[0058] Diseases or conditions that may be treated by using the drugdelivery system and methods of the present invention include, but arenot limited to chronic pain conditions, post-operative pain, restlessleg syndrome, opioid dependence and neuropathic pain.

[0059] The drug delivery system of the present invention may be appliedto the skin by means of an aerosol, spray, pump-pack, brush, swab, orother applicator. Preferably, the applicator provides either a fixed orvariable metered dose application such as a metered dose aerosol, astored-energy metered dose pump or a manual metered dose pump.Preferably the drug delivery system is applied to the skin of the humanor animal covering a delivery surface area between about 10 and 800 cm²,more preferably between about 10 and 400 cm², and most preferably about10 and 200 cm². The application is most preferably performed by means ofa topical metered dose spray combined with an actuator nozzle shroudwhich together accurately control the amount and/or uniformity of thedose applied. One function of the shroud is to keep the nozzle at apre-determined height above, and perpendicular to, the skin to which thedrug delivery system is being applied. This function may also beachieved by means of a spacer-bar or the like. Another function of theshroud is to enclose the area above the skin in order to prevent orlimit bounce-back and/or loss of the drug delivery system to thesurrounding environment. Preferably the area of application defined bythe shroud is substantially circular in shape.

[0060] The drug delivery system may be propelled by either pump pack orby the use of propellants such as hydrocarbons, hydro fluorocarbons,nitrogen, nitrous oxide, carbon dioxide or ethers, preferably dimethylether. The drug delivery system is preferably in a single phase systemas this allows less complicated manufacture and ease of dose uniformity.It may also be necessary to apply a number of dosages on untreated skinto obtain the desired result.

DETAILED DESCRIPTION OF THE INVENTION

[0061] The invention will now be described with reference to thefollowing examples and accompanying FIGURE. The examples and FIGURE arenot to be construed as limiting the invention in any way. They areincluded to further illustrate the present invention and advantagesthereof.

In the accompanying FIGURE:

[0062]FIG. 1 Shows the cumulative amount of fentanyl penetrating acrosshuman epidermis (μg/cm²) versus time (hours) for the transdermal spraycomposition 1A with or without the dermal penetration enhancer, octylsalicylate. Error bars represent Standard Error of the Mean (SEM).

[0063] In the examples, the effectiveness of the penetration enhancersare illustrated by measuring the skin penetration of formulations of anumber analgesics with the dermal penetration enhancers. Also, the skinpenetration of analgesics is measured with other prior art penetrationenhancers as well as formulations of the analgesics with commonadjuvants, which serve as control formulations. The comparisonsgenerally consist of measuring the relative penetration through shedsnake skin of the various formulations. In every case, thoseformulations which contain the dermal penetration enhancers deliver moreof the analgesic through the skin than the corresponding controlformulation.

EXAMPLE 1

[0064] Topical Spray Compositions Composition 1A Composition 1BComponent Amount Component Amount Fentanyl 7.5% w/v Fentanyl 7.5% w/vOctyl salicylate   5% w/v Padimate O   6% w/v Aqueous ethanol to 100 mLAqueous ethanol to 100 mL (95% v/v) (95% v/v)

EXAMPLE 2

[0065] Topical Spray Compositions Composition 2A Composition 2BComponent Amount Component Amount Fentanyl 5% w/v Fentanyl 2.5% w/vOctyl salicylate 5% w/v Octyl Salicylate   5% w/v Aqueous ethanol to 100mL Aqueous ethanol to 100 mL (95% v/v) (95% v/v)

EXAMPLE 3

[0066] Enhanced skin penetration of fentanyl base using octyl salicylatein a transdermal spray composition (Composition 1A).

[0067] As shown in FIG. 1 the addition of the safe sunscreen esterdermal penetration enhancer, octyl salicylate, surprisingly causes amarked 4-fold increase in the transdermal delivery of fentanyl acrossthe skin (p<0.05).

[0068] The diffusion experiments are performed using human epidermis asthe model membrane. These experiments are performed over 24 h withstainless steel, flow-through diffusion cells based on those previouslydescribed, (Cooper, E. R. J. Pharm. Sci. 1984, 73, 1153-1156.) exceptthat the cell is modified to increase the diffusional area to 1.0 cm².The formulations are applied using a finite dose technique (Franz, T. J.Curr. Probl. Dermatol. 1978, 7, 58-68.) to mimic clinical dosingconditions at an applied dose volume of 5 μL/cm². A piece of stainlesssteel wire mesh is placed directly below the skin in the receptorchamber of the diffusion cell to maintain a turbulent flow of receptorsolution below the skin. The diffusion cells are maintained at a flowrate of approximately 1.0 mL/cm²/h by a microcassette peristaltic pump(Watson Marlow 505S, UK). The cells are kept at 32±0.5° C. by a heaterbar and the samples are collected into appropriately sized plastic vialson an automated fraction collector (Isco Retriever II, Lincoln, Nebr.)at specified intervals. The receptor solution (0.002% w/v sodium azidein water) maintains sink conditions beneath the skin.

[0069] Samples are analysed for fentanyl directly by RP-HPLC using theconditions shown in Table 1. TABLE 1 Chromatographic conditions used foranalysis of fentanyl Column Waters Symmetry C₁₈ column (3.9 × 150 mm)with a 5 μm particle size Mobile Phase Solvent A: Acetonitrile inaqueous 0.009% perchloric acid (1 in 10) with 9 mM 1-Heptanesulfonicacid sodium salt Solvent B: Acetonitrile Flow rate  1.0 mL/minAbsorbance 210 nm Injection volume  50 μL Gradient method Time (min)Solvent A Solvent B 0 80 20 8.5 63 37 9 80 20 11 80 20

EXAMPLE 4

[0070] Topical Gel Compositions Composition 3A Composition 3B ComponentAmount Component Amount Fentanyl  2.5% w/v Fentanyl  2.5% w/v Octylsalicylate   1% w/v Padimate O   2% w/v Carbopol  0.9% w/v Carbopol 0.9% w/v 0.1 N NaOH 4.72% w/v 0.1 N NaOH 4.72% w/v Aqueous ethanol to100 mL Aqueous ethanol to 100 mL (70% v/v) (70% v/v)

EXAMPLE 5

[0071] Topical Lotion Compositions Composition 4A Composition 4BComponent Amount Component Amount Fentanyl 2.5% w/v Fentanyl 2.5% w/vOctyl salicylate 2.5% w/v Padimate O   3% w/v Hydroxy propyl 1.5% w/vEthyl cellulose 1.5% w/v cellulose Aqueous ethanol to 100 mL Aqueousethanol to 100 mL (90% v/v) (90% v/v)

We claim:
 1. A transdermal drug delivery system comprising: (a) atherapeutically effective amount of an analgesic hormone; (b) at leastone dermal penetration enhancer, which is a safe skin-tolerant estersunscreen of formula (I):

wherein R¹ is hydrogen, lower alkyl, lower alkoxy, halide, hydroxy orNR³ R⁴; R² is a C₈ to C₁₈ alkyl; R³ and R⁴ are each independentlyhydrogen, lower alkyl or R³ and R⁴ together with the nitrogen atom towhich they are attached form a 5- or 6-membered heterocyclic ring; n is0 or 1, and q is 1 or 2, wherein, when n is 0 and R¹ is R³ R⁴, then R³R⁴ is para-substituted, and wherein said dermal penetration enhancer ispresent in an amount of from about 10 to about 10,000 wt % based on theweight of the hormone; and (c) at least one volatile liquid.
 2. Thetransdermal drug delivery system according to claim 1, wherein thedermal penetration enhancer is octyl salicylate.
 3. The transdermal drugdelivery system according to claim 1, wherein the volatile liquid isselected from the group consisting of ethanol, isopropanol, and amixture thereof.
 4. The transdermal drug delivery system according toclaim 1, comprising on a weight basis: (a) from about 0.1 to about 10%of said analgesic; (b) from about 0.1 to about 10% of said at least onedermal penetration enhancer; and (c) from about 80 to about 99.8% ofsaid volatile liquid.
 5. The transdermal drug delivery system accordingto claim 1, wherein the analgesic is selected from the group consistingof opium, butorphanol, dezocine, diamorphine, hydrocodone, ketobemidone,levomethadyl acetate, mepiridine, nalbuphine, piritramide, remifentanil,tilidine, meptazinol, dezocine, eptazocine and flupirtine.
 6. Thetransdermal drug delivery system according to claim 1, wherein theanalgesic is selected from the group consisting of tramadol,dextromoramide, dextropropoxyphene, alfentanil, sufentanil,hydromorphone, methadone, morphine, oxycodone, papaveretum, pentazocine,pethidine, phenoperidine, codeine and dihydrocodeine.
 7. The transdermaldrug delivery system according to claim 1, wherein the analgesic isselected from the group consisting of buprenorphine and fentanyl.
 8. Thetransdermal drug delivery system according to claim 7, wherein theanalgesic is fentanyl.
 9. The transdermal drug delivery system accordingto claim 8, comprising on a weight basis: (a) from about 1 to about 10%fentanyl; (b) from about 1 to about 10% octyl salicylate; and (c) fromabout 80 to about 98% Alcohol USP (95% ethanol).
 10. The transdermaldrug delivery system according to claim 8, comprising on a weight basis:(a) from about 1 to about 5% fentanyl; (b) from about 1 to about 5%octyl salicylate; and (c) from about 45 to about 90% of a volatileliquid selected from the group consisting of ethanol, isopropanol, and amixture thereof; (d) from about 5 to about 45% water; and (e) from about0.5 to about 5% of a thickening agent.
 11. A method for administering atleast one systemic acting analgesic to an animal which comprisesapplying an effective amount of the analgesic in the form of the drugdelivery system according to claim
 1. 12. The method according to claim11, wherein the analgesic is selected from the group consisting ofopium, butorphanol, dezocine, diamorphine, hydrocodone, ketobemidone,levomethadyl acetate, mepiridine, nalbuphine, piritramide, remifentanil,tilidine, meptazinol, dezocine, eptazocine and flupirtine.
 13. Themethod according to claim 11, wherein the analgesic is selected from thegroup consisting of tramadol, dextromoramide, dextropropoxyphene,alfentanil, sufentanil, hydromorphone, methadone, morphine, oxycodone,papaveretum, pentazocine, pethidine, phenoperidine, codeine anddihydrocodeine.
 14. The method according to claim 11, wherein theanalgesic is selected from the group consisting of buprenorphine andfentanyl.
 15. The method according to claim 14, wherein the analgesic isfentanyl.
 16. The method according to claim 11, wherein the drugdelivery system is applied to the skin of the animal covering a deliverysurface area between about 10 and 800 cm².
 17. The method according toclaim 11, wherein the drug delivery system is applied to the skin of theanimal covering a delivery surface area between about 10 and 400 cm².18. The method according to claim 11, wherein the drug delivery systemis applied to the skin of the animal covering a delivery surface areabetween about 10 and 200 cm².
 19. The method according to claim 11,wherein the drug delivery system is applied using a fixed or variablemetered dose applicator.